Insulin is the major hormone regulating in vivo glucose metabolism and abnormalities of insulin action are central to the pathogenesis of a variety of abnormal physiologic states. Consequently knowledge of the cellular mechanisms of insulin's effect on glucose metabolism will lead to a better understanding of the mechanisms of a variety of diseases. Techniques are now available to study many of the cellular events involved in insulin action, and the overall goal of this research proposal is to investigate various aspects of the interaction between insulin and the glucose transport system. Insulin activates the glucose transport system by increasing the apparent Vmax of transport without affecting the Km (Kt) and we plan to investigate whether this effect occurs through an increase in the number of glucose transport units, or an increase in the mobility of existing units. A mathematical model describing functions for the interaction between insulin receptors and the glucose transport system will be developed and tested, and will be applied to the understanding of abnormalities of this interaction in abnormal physiologic states. Furthermore, the temporal relationship between the formation and dissociation of insulin receptors complexes and the onset and termination of insulin's effect on glucose transport will be characterized, and the possible role of changes in cellular calcium metabolism as an intermediate event (coupling) in insulin's activation of glucose transport will be investigated. Finally, the role of insulin in the long-term regulation of the capacity of the glucose transport system will be studied. These studies will lead to a better understanding of the cellular events underlying insulin's ability to activate glucose transport, and should sharpen our understanding of the mechanisms of disease states in which insulin action is abnormal.